College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China; School of Pharmaceutical Science, Hunan University of Chinese Medicine, Changsha, 410208, China.
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Eur J Med Chem. 2021 Mar 5;213:113161. doi: 10.1016/j.ejmech.2021.113161. Epub 2021 Jan 12.
A series of 4-thiazolinone derivatives (D1-D58) were designed and synthesized. All of the derivatives were evaluated in vitro for neuraminidase (NA) inhibitory activities against influenza virus A (H1N1), and the inhibitory activities of the five most potent compounds were further evaluated on NA from two different influenza viral subtypes (H3N2 and B), and then their in vitro anti-viral activities were evaluated using the cytopathic effect (CPE) reduction assay. The results showed that the majority of the target compounds exhibited moderate to good NA inhibitory activity. Compound D18 presented the most potent inhibitory activity with IC values of 13.06 μM against influenza H1N1 subtype. Among the selected compounds, D18 and D41 turned out to be the most potent inhibitors against influenza virus H3N2 subtype (IC = 15.00 μM and IC = 14.97 μM, respectively). D25 was the most potent compound against influenza B subtype (IC = 16.09 μM). In addition, D41 showed low toxicity and greater potency than reference compounds Oseltamivir and Amantadine against N1-H275Y variant in cellular assays. The structure-activity relationship (SAR) analysis showed that introducing 4-COH, 4-OH, 3-OCH-4-OH substituted benzyl methylene can greatly improve the activity of 4-thiazolinones. Further SAR analysis indicated that 4-thiazolinone and ferulic acid fragments are necessary fragments of target compounds for inhibiting NA. Molecular docking was performed to study the interaction between compound D41 and the active site of NA. This study may providing important information for new drug development for anti-influenza virus including mutant influenza virus.
设计并合成了一系列 4-噻唑啉酮衍生物（D1-D58）。所有衍生物均在体外针对甲型流感病毒神经氨酸酶（NA）抑制活性进行了评估，对其中五个活性最强的化合物在来自两种不同流感病毒亚型（H3N2 和 B）的 NA 上的进一步评估，然后使用细胞病变效应（CPE）减少测定法评估其体外抗病毒活性。结果表明，大多数目标化合物表现出中等至良好的 NA 抑制活性。化合物 D18 对甲型流感 H1N1 亚型的抑制活性最强，IC 值为 13.06 μM。在所选择的化合物中，D18 和 D41 对流感病毒 H3N2 亚型表现出最强的抑制活性（IC = 15.00 μM 和 IC = 14.97 μM）。D25 是对乙型流感亚型最强的化合物（IC = 16.09 μM）。此外，D41 在细胞测定中对 N1-H275Y 变体的毒性低于参考化合物奥司他韦和金刚烷胺，且活性更强。构效关系（SAR）分析表明，引入 4-COH、4-OH、3-OCH-4-OH 取代的苄叉甲基可大大提高 4-噻唑啉酮的活性。进一步的 SAR 分析表明，4-噻唑啉酮和阿魏酸片段是抑制 NA 的目标化合物的必要片段。进行了分子对接以研究化合物 D41 与 NA 活性位点之间的相互作用。这项研究可能为包括突变流感病毒在内的抗流感病毒新药开发提供重要信息。
